Cancer is a major world problem. Every year nearly 6 million new patients are diagnosed and more than 5 millions die. For patients suffering of cancer pain is a common problem and an analysis of 32 published reviews revealed that 70% of patients with advanced cancer had pain as a major symptom. From available data it is not possible to give a precise figure for the world-wide prevalence of cancer pain because the total number of cancer patients receiving treatment is not known. A conservative estimate is that every day at least 3.5 million people are suffering from cancer pain. This pain is an important but neglected public health issue in developed and developing countries. Effective pain management particularly in patients with advanced disease is one of four priorities in a comprehensive WHO cancer programme. According to this programme morphine is the drug of choice for patients with advanced disease having such severe pains that they need a strong opioid. It has thus been found that morphine is both efficacious and acceptable.
Opioids such as morphine must be administered in an acceptable form. The oral route is the best, because it spares the patient the discomfort of injections; it also maintains the patient's independence, since he or she does not have to rely on someone else for the next dose.
Morphine can be administered as a simple aqueous solution of morphine sulphate (or hydrochloride) in a range of strengths (e.g. 1 mg of morphine sulphate per ml to 20 mg per ml).
The effective analgesic dose of morphine varies considerably and ranges from as little as 5 mg to more than 200 mg. In many patients, pain is satisfactorily controlled with doses of between 5 and 30 mg every 4 hours. However, the dosage varies greatly for different patients because of wide individual variations in the oral bioavailability of the drug; the appropriate dose is the one that works. The drug must be given by the clock, i.e. at regular intervals, and not only when the patient complains of pain. The use of morphine is dictated by intensity of pain and not by brevity of prognosis.
Sustained-release morphine tablets are available in some countries in strengths varying from 10 to 200 mg. The most widely available strength is 30 mg. The dominating product is called a.o. MST Continus, MS Contin or MST. In vitro release data as well as pharmacokinetic data for this product, showing a major part of the active ingredient released and absorbed already within the first two or three hours, suggest that its properties are not adequate for a convenient dose schedule. While the manufacturer recommends up to 12-hours dosing intervals, extensive clinical experience suggests that an 8-hours interval is more realistic for continuous pain control.
In order to avoid pain periods due to inadequate compliance and to keep the patient constantly pain free, the administration of the analgesic drug must interfere as little as possible with the daily life. Twice daily administration is a reasonable solution but once daily administration is the ultimate goal. Another reason for developing preparations of long duration is that the patients in question are often very sick and need assistance for the medication. It would therefore be advantageous both for the patient and for the medical staff if a preparation for once a day administration would be available.
However, up to now it has not been considered feasible to make an oral morphine controlled release preparation which can be taken less than twice a day and still provide satisfactory bioavailablity, satisfactorily high plasma levels and pain relief. It has thus been considered that morphine can be sufficiently absorbed only during the comparatively short period when the morphine is in the stomach and small intestine from which follows that it would not be possible to make a morphine preparation which can be administered once per 24 hours and-still give effective pain relief.
It has furthermore been considered impossible to make oral preparations with good controlled release properties from drug substances with high aqueous solubility, such as morphine sulphate. In the European Patent Application 0 377 518 it is suggested that sustained release preparations of highly soluble active substances such as morphine sulphate should be prepared with different release rates in the stomach and in the intestine, the active substance being available for absorption at a relatively faster rate in the intestine.
Other patent publications disclosing morphine preparations are the European Patent Publications 97 523 and 205 282, the U.S. Pat. Nos. 4,461,598 and 4,970,075 as well as the DD patent publications 295 548.